title: Preparation and evaluation of itraconazole dihydrochloride for the solubility and dissolution rate enhancement.
abstract: The purpose of this work was to explore the feasibility of preparing itraconazole hydrochloride to improve the solubility and dissolution rate. Itraconazole dihydrochloride was synthesized by bubbling anhydrous hydrogen chloride gas into the acetone suspension of itraconazole. Results of the elementary analysis gave the molecular formula of C(35)H(38)Cl(2)N(8)O(4).2HCl and its structure was confirmed by Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-Ray diffraction (PXRD) suggested that a new crystalline form of the salt was formed. The morphology and mean size distribution study by scanning electron microscopy (SEM) and dynamic light scattering (DLS) confirmed that the salt was dispersable nanoparticle aggregation. Aqueous solubility measurements showed that the solubility of the salt, its 1:1, 1:2 and 1:3 (w/w) physical mixtures with beta-cyclodextrin (beta-CD) was 6, 99, 236 and 388 times greater than itraconazole. More than 94% of itraconazole was dissolved out of the salt/beta-CD 1/3 physical mixture after 60min. The stability studies indicated that the physical mixture remained stable for 24 months in assay, the related substances and dissolution. Based on the present results, it is concluded that hydrochloride formation can significantly increase solubility and dissolution rate of itraconazole, and the formulation of itraconazole dihydrochloride/beta-CD (1/3) would be an environment-friendly, economic and practical alternative to the commercially available itraconazole capsules (Sporanox)
authors.affiliation: Department of Pharmaceutics, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road, Shanghai, PR China. taotaosipi@hotmail.com
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jinjin
authors.initials: J
authors.lastname: Wu
authors.forename: Beiyi
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000737:chemistry; D000935:Antifungal Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D017964:Itraconazole / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000277:Adjuvants, Pharmaceutic; D000935:Antifungal Agents; D047392:beta-Cyclodextrins; D017964:Itraconazole; C031215:betadex